Pulmonary surfactant (also referred to as “lung surfactant”) is a complex mixture of lipids and proteins that promote the formation of a monolayer at the alveolar air-water interface, and by reducing the surface tension, prevents the collapse of the alveolus during expiration. Lung surfactant lines the alveolar epithelium of mature mammalian lungs. Natural lung surfactant has been described as a “lipoprotein complex” because it contains both phospholipids and apoproteins that interact to reduce surface tension at the lung air-liquid interface. Four proteins have been found to be associated with lung surfactant, namely SP-A, SP-B, SP-C, and SP-D. Specifically, SP-B appears to be essential for the biophysical action of lung surfactant. It is accepted therapy for the treatment of a variety of respiratory disorders to administer lung surfactant to the patient's lungs.
From a pharmacological point of view, the optimal exogenous lung surfactant to use in the treatment would be completely synthesized in the laboratory. In this regard, one mimetic or mimic of SP-B that has found to be useful is KL4, which is a 21 amino acid cationic polypeptide.
One method of manufacturing lung surfactant on a commercial-scale for medical use is by a process that utilizes a thin film evaporator (TFE) unit operation. The process as it applies to the production of KL4 lung surfactant consists of the following steps: 1) solubilizing the four primary formulation components, dipalmitoyl phosphatidylcholine (DPPC), palmitoyloleoyl phosphatidylglycerol (POPG) and palmitic acid (PA) and KL4 in ethanol; 2) removing the ethanol utilizing the TFE; and 3) vialing the final dispersion. The TFE unit operation itself is complex and has scaling limitations. Specifically, a 1 ft2 TFE produces a 40-liter batch and the biggest comparable unit available is a 10 ft2 TFE. This restricts the batch size which is undesirable as additional indications are approved for the KL4 surfactant requiring ever increasing amounts of surfactant. Moreover, the process is performed under aseptic conditions that contribute significantly to the cost, scheduling flexibility, and complexity of the product.
In addition to the cost and complexity of using a TFE, a further complication exists due to the composition being stored in a liquid state. Because the polypeptide and lipid components of the composition are subject to degradation, the solution must be kept refrigerated to retard any degradation and achieve long term stability.
It is well known in the art that lyophilizing products, such as injectable pharmaceuticals, which are relatively unstable in aqueous solution can result in solid phase products that are more stabile and therefore have a longer shelf life. Examples of pharmaceuticals that are lyophilized include alprostadil, alplidine, beta-interferon, amoxicillin sodium, tobramycin sulfate, gentamicin sulfate, cardiotonic phosphodiesterase inhibitors, cyclohexane-1,2-diaminePt(II) complex, annamycin, fructose-1,6-diphosphate, and the like.
In order to provide a KL4 pulmonary surfactant with improved stability at room temperature, attempts have been made to lyophilize the surfactant composition as described in U.S. Pat. No. 5,952,303. However, there is a need for improved methods of producing lung surfactant compositions and improved lung surfactant compositions. The present invention is directed to this and other important ends.